Resmetirom and GLP-1 agonists for MASH: complementary rather than exclusive

Abstract

Developing drugs for metabolic dysfunction-associated steatohepatitis (MASH) has been a surprisingly challenging task. To effectively treat MASH, the drug should address the three key issues associated with these conditions: fat accumulation, inflammation, and fibrosis. However, no therapeutic drugs have been able to meet all the required criteria, especially when it comes to improving fibrosis. With FDA approval, resmetirom, a liver-targeted thyroid hormone receptor-β (THRβ) selective agonist, changes the MASH drug development landscape. The activation of THRβ is known to improve MASH by controlling fat synthesis, regulating fatty acid oxidation, cholesterol metabolism, mitochondrial function, and reducing inflammation and fibrosis. Glucagon-like peptide-1 (GLP-1) agonists, employed to treat diabetes and obesity, has been tested on MASH patients and is widely regarded as the preferred treatment for MASH. GLP-1 agonists are regarded as the primary contenders for resmetirom. Some even suggest that GLP-1 agonists might have the potential to supplant MASH therapy in its entirety. It should be noted that while GLP-1 agonists positively impact metabolism upstream of the liver, this may not subsequently improve the fibrotic liver injury within the tested treatment duration. Combining the therapeutic approaches of GLP-1 agonists (which target extrahepatic mechanisms for metabolic disorders) with resmetirom (which target intrahepatic mechanisms for MASH and liver fibrosis) seems like a promising strategy for addressing fat accumulation, inflammation, and fibrosis associated with MASH.